The present invention relates to amino acid-derived bioerodible polymers and to methods of synthesizing such polymers. In particular, the present invention relates to bioerodible polyarylates derived from the natural amino acid L-tyrosine and biocompatible dicarboxylic acids.
Polyesters in general are highly useful and intensively studied materials. Polyesters have been classified according to the nature of the polyhydric compounds and dicarboxylic acids from which the polymers are derived. Polyesters derived from aromatic polyhydric compounds are classified as polyarylates, with polyarylates of aliphatic diacids classified as aliphatic polyarylates and polyarylates of aromatic diacids classified as aromatic polyarylates. Polyesters derived from aliphatic polyhydric compounds and aliphatic diacids are classified as aliphatic polyesters, and polyesters derived from aliphatic polyhydric compounds and aromatic diacids are classified as aliphatic-aromatic polyesters. See Imai et al., "Synthesis and Characterization of Aromatic Polyesters," Handbook of Polymer Science and Technology, Vol. 1, N. Cheremisinoff, ed., Marcel Dekker, Inc., New York and Basel, 1989) , 177-208.
A wide range of aliphatic polyesters (e.g., poly(lactic acid), poly(glycolic acid), polydioxanone, poly(hydroxybutyrate), polycapro-lactone and the like) have been explored as biomaterials, especially in the context of degradable medical implants because of their hydrolyric instability. See, Huang, "Biodegradable Polymers," Encyclopedia of Polymer Science and Technology, (F. H. Mark et al., ed., John Wiley and Sons, New York 1985), vol. 2, 220-43. Because of their hydrolyric instability, however, aliphatic polyesters are not used as industrial engineering plastics.
Aliphatic-aromatic polyesters include poly(ethylene terephthalate) (PET) and poly(butylene terephthalate) (PBT). Some aliphatic-aromatic polyesters are very important commercial plastics, but (with the exception of DACRON.RTM.) have not been widely investigated in the biomaterials area. DACRON.RTM.is a PET used as an artificial vascular graft. See, Silver et al., Biocompatibility: Interactions of Biological and Implantable Materials, vol. 1, (VCH Publishers, New York, 1989) 240-3. Aliphatic-aromatic polyesters are hydrolytically much more stable than aliphatic polyesters and are degraded under physiological conditions at such a slow rate that they are regarded as "nondegradable."
Aromatic polyarylates have recently gained importance as liquid crystalline polymers. These polymers are derived from aromatic dicarboxylic acids and diphenols (bisphenols). Many aromatic polyarylates possess highly desirable properties for use as engineering plastics, such as formation of strong films and fibers which are heat, solvent and flammability resistant.
In addition, some aromatic polyarylates are electric insulators and exhibit liquid crystalline behavior. For example, Carborundum marketed poly(p-hydroxybenzoic acid) under the trade name of EKKONOL.RTM. in 1970. Shortly thereafter, ICI, Tennessee Eastman, Celanese and DuPont marketed polyarylates derived from iso- and terephthalic acids and bisphenols such as hydroquinone, substituted hydroquinones and Bisphenol A. See, Gaudiana, "Polyesters, Main Chain Aromatic," Encyclopedia of Polymer Science and Engineering, (Mark et al., ed., John Wiley and Sons, New York, 1985) vol. 2, 264-6. The major disadvantage of these early polyarylates was that they were difficult to process because of their high melting points. More recently, new polyarylates that are more easily processable have been obtained through modification of the monomers, copolymerization and blending.
Aliphatic polyarylates are a fourth class of polyester and are derived from aromatic diols and aliphatic diacids. Examples of aliphatic polyarylates include poly(hydroquinone-adipate) and poly(Bisphenol A-sebacate). These polymers have less commercial appeal because they do not generally possess the high thermal stability of the aromatic polyarylates. The synthesis of aliphatic polyarylates from bisphenols and aliphatic dicarboxylic acids was first reported by British Patent Nos. 621,102 and 636,429. In the early work, hydroquinone and aliphatic dicarboxylic acids were used to develop aliphatic polyarylates of high melting points and hydrolytic stability. See, Eareckson, J. Polym. Sci., 40, 399-406 (1959), Egorova et al., Vysokomolekul. Soedin., 2, 1475 (1960) and Mikhailov et al., Khim Volokna, 1963(2), 19-22 (1963).
Particularly important are the studies of Morgan, J. Polym. Sci., Part A2, 437-59 (1964) who synthesized a series of aliphatic polyarylates using either phenolphthalein or Bisphenol A as the diphenol components. By varying the length of the diacid, Morgan established the first systematic structure-property correlations for this class of polymers. Morgan noted that all the polymers prepared were amorphous, soluble in a variety of organic solvents, and had relatively low softening temperatures. Thus, these materials were not the high temperature engineering plastics sought by industry. Many other aliphatic polyarylates were later synthesized, for example, from resorcinol, dihydroxynapthalenes, bis(4-hydroxyphenyl) alkanes and phthaleins. See, Morgan, Condensation Polymers: By Interfacial and Solution Methods, (Interscience Publishers, New York, 1965) 334-41.
Commonly owned U.S. Pat. No. 5,099,060 discloses amino acid-derived diphenol compounds, the chemical structures of which were designed to be particularly useful in the polymerization of polycarbonates and polyiminocarbonates. The resulting polymers are useful as degradable polymers in general, and as tissue compatible bioerodible materials for biomedical uses, in particular. The suitability of these polymers for this end-use application is the result of their derivation from naturally occurring amino acids. In particular, the polyiminocarbonates and polycarbonates are polymerized from L-tyrosine derived diphenols.
The L-tyrosine derived polyiminocarbonates are rapidly biodegradable, while their polycarbonate counterparts degrade very slowly. This patent suggests that when a material having a moderate degree of bioerodibility is required, that the two polymers be blended to achieve the required rate of biodegradation. While this adequately addresses this requirement, a need remains for biodegradable polymers having a moderate rate of hydrolytic degradation.
Aliphatic polyarylate type polyesters would be expected to have a moderate rate of biodegradation. Such compounds could be prepared from the L-tyrosine derived diphenols used in the preparation of the polycarbonates and polyiminocarbonates disclosed by U.S. Pat. No. 5,099,060. However, unlike the polycarbonates and polyiminocarbonates, which are polymerized by linking biocompatible amino acid-derived diphenols by way of non-amide linkages to provide a nontoxic polymer that forms nontoxic degradation products, the polymerization of polyesters requires the reaction of a diacid with the diphenol. Diacids are therefore also required that will produce a nontoxic polymer that forms nontoxic degradation products.
There is no disclosure in the prior art that tyrosine-derived diphenols specifically designed for the polymerization of mechanically strong polyiminocarbonates and polycarbonates would also form polyarylates with favorable engineering properties when reacted with various aliphatic and aromatic dicarboxylic acids. Furthermore, the synthesis of polyarylates using the amino acid-derived diphenols of U.S. Pat. No. 5,099,060 poses a challenge because of the relative inertness of these diphenols in polyesterifications and because of the presence of a chemically sensitive aliphatic ester bond in the monomer structure. Contrary to the formation of aliphatic polyesters in which the thermodynamic equilibrium favors esterification, the synthesis of polyarylates requires the activation of the diacid. Traditional methods of synthesis utilize diacid chloride derivatives as the active intermediates in either solution or interfacial polymerization reactions. Transesterifications at elevated temperatures and direct polycondensations using a variety of condensing agents have also been explored. See, Imai et al., "Synthesis and Characterization of Aromatic Polyesters," Handbook of Polymer Science and Technoloqy.
Aliphatic polyarylates of intermediate molecular weight (inherent viscosity about 0.52) were prepared by Morgan, J. Polym. Sci., Part A2, 437-59 (1964) under mild conditions of low temperature and pressure, through the diacid chloride and direct polycondensation routes. In the diacid chloride interfacial reaction a strongly basic aqueous solution of the bisphenolate anion is reacted with a solution of a diacid chloride in a water-immiscible organic solvent such as dichloromethane. The reaction occurs at the interface and is accelerated by the use of a quaternary ammonium or phosphonium salt or by a phase transfer catalyst such as a crown ether. See, Conix, Ind Eng. Chem., 51, 147 (1959). The diacid chloride reaction can also be done in an organic solvent and a base such as triethylamine is often used to neutralize liberated hydrogen chloride. See, Morgan, J. Polym. Sci., Part A2, 437-59 (1964).
The direct polycondensation route has significant advantages over the diacid chloride technique in the laboratory preparation of aliphatic polyarylates. The need for the unstable diacid chlorides is eliminated, and the diphenol can have functional groups that would be incompatible with the reactive diacid chlorides or the strongly basic aqueous solutions required in the interfacial technique. Direct polycondensation thereby facilitates the use of base-sensitive diphenols as monomers, such as the amino acid-derived diphenols disclosed in U.S. Pat. No. 5,099,060.
A variety of condensing agents have been used in the polymerization of aliphatic polyarylates, including triphenylphosphine (see, Ogata et al., Polym. J., 13 (10), 989-91 (1981) and Yasuda et al., J. Polym. Sci.: Polym. Chem. Ed., 21, 2609-16 (1983)) , picryl chloride (see, Tanaka et al., Polym. J., 14 (8), 643-8 ( 1982 )) , phosphorus oxychloride with lithium chloride monohydrate as a catalyst (see, Higashi et al., J. Polym. Sci.: Polym. Chem. Ed., 24, 589-94 (1986)), arylsulfonyl chlorides (see, Higashi et al., J. Polym. Sci.: Poly. Chem. Ed., 21, 3233-9 (1983)), diphenyl chlorophosphate (see, Higashi et al., J. Polym. Sci.: Polym. Chem. Ed., 21, 3241-7 (1983)), thionyl chloride with pyridine (see, Higashi, J. Polym. Sci.: Polym. Chem. Ed., 24, 97-102 (1986)), triethylamine as a base (see Elias et al., Makromol. Chem., 182, 681-6 (1981)) and diisopropylcarbodiimide with the specially designed catalyst 4-(dimethylamino) pyridinium 4-toluenesulfonate (DPTS) (see, Moore et al., Macromol., 23 (1), 65-70 (1990)). Although numerous aliphatic polyarylates have thus been prepared, they have usually been derived from bioincompatible diacid or hisphenol components and would therefore not be expected to be suitable as degradable medical implant materials.
There remains a need for nontoxic polyarylates having a moderate rate of bioerosion, suitable for use as tissue-compatible materials for biomedical uses.